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Leptin modulates the expression of secreted and membrane-associated mucins in colonic epithelial cells by targeting PKC, PI3K, and MAPK pathways
Mucins play an essential role in the protection and repair of gastrointestinal mucosa. We recently showed that luminal leptin strongly stimulated mucin secretion in vivo in rat colon. In the present study, we challenged the hypothesis that leptin may act directly on goblet cells to induce mucin expr...
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| Published in: | American journal of physiology: Gastrointestinal and liver physiology 2007-07, Vol.293 (1), p.G365-G373 |
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| container_end_page | G373 |
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| container_title | American journal of physiology: Gastrointestinal and liver physiology |
| container_volume | 293 |
| creator | El Homsi, Mahmoud Ducroc, Robert Claustre, Jean Jourdan, Gérard Gertler, Arieh Estienne, Monique Bado, André Scoazec, Jean-Yves Plaisancié, Pascale |
| description | Mucins play an essential role in the protection and repair of gastrointestinal mucosa. We recently showed that luminal leptin strongly stimulated mucin secretion in vivo in rat colon. In the present study, we challenged the hypothesis that leptin may act directly on goblet cells to induce mucin expression in rat and human intestinal mucin-producing cells (DHE and HT29-MTX). The endoluminal effect of leptin was also studied in vivo in rat perfused colon model. The presence of leptin receptors was demonstrated in the two cell lines by Western blot and RT-PCR. In rat DHE cells, leptin (0.01-10 nmol/l, 60 min) dose dependently increased the secretion of mucins (210 +/- 3% of controls) and the expression of Muc2, Muc3, and Muc4 (twofold basal level) but not of Muc1 and Muc5AC. Luminal perfusion of leptin (60 min, 0.1-100 nmol/l) in rat colon also increased the mRNA level of Muc2, Muc3, and Muc4 but not of Muc1. In human HT29-MTX cells, leptin (0.01-10 nmol/l, 60 min) dose dependently enhanced MUC2, MUC5AC, and MUC4 mRNA levels. These effects were prevented by pretreatment of cells with the leptin mutein L39A/D40A/F41A, which acts as a receptor antagonist. Finally, pathway inhibition experiments suggest that leptin increased mucin expression by activating PKC-, phosphatidyl inositol 3-kinase-, and MAPK-dependent pathways but not the JAK/STAT pathway. In conclusion, leptin may contribute significantly to membrane-associated and secreted mucin production via a direct stimulation of colonic epithelial cells and the activation of leptin receptors. These data are consistent with a role for leptin in regulation of the intestinal barrier function. |
| doi_str_mv | 10.1152/ajpgi.00091.2007 |
| format | article |
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We recently showed that luminal leptin strongly stimulated mucin secretion in vivo in rat colon. In the present study, we challenged the hypothesis that leptin may act directly on goblet cells to induce mucin expression in rat and human intestinal mucin-producing cells (DHE and HT29-MTX). The endoluminal effect of leptin was also studied in vivo in rat perfused colon model. The presence of leptin receptors was demonstrated in the two cell lines by Western blot and RT-PCR. In rat DHE cells, leptin (0.01-10 nmol/l, 60 min) dose dependently increased the secretion of mucins (210 +/- 3% of controls) and the expression of Muc2, Muc3, and Muc4 (twofold basal level) but not of Muc1 and Muc5AC. Luminal perfusion of leptin (60 min, 0.1-100 nmol/l) in rat colon also increased the mRNA level of Muc2, Muc3, and Muc4 but not of Muc1. In human HT29-MTX cells, leptin (0.01-10 nmol/l, 60 min) dose dependently enhanced MUC2, MUC5AC, and MUC4 mRNA levels. These effects were prevented by pretreatment of cells with the leptin mutein L39A/D40A/F41A, which acts as a receptor antagonist. Finally, pathway inhibition experiments suggest that leptin increased mucin expression by activating PKC-, phosphatidyl inositol 3-kinase-, and MAPK-dependent pathways but not the JAK/STAT pathway. In conclusion, leptin may contribute significantly to membrane-associated and secreted mucin production via a direct stimulation of colonic epithelial cells and the activation of leptin receptors. 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These effects were prevented by pretreatment of cells with the leptin mutein L39A/D40A/F41A, which acts as a receptor antagonist. Finally, pathway inhibition experiments suggest that leptin increased mucin expression by activating PKC-, phosphatidyl inositol 3-kinase-, and MAPK-dependent pathways but not the JAK/STAT pathway. In conclusion, leptin may contribute significantly to membrane-associated and secreted mucin production via a direct stimulation of colonic epithelial cells and the activation of leptin receptors. These data are consistent with a role for leptin in regulation of the intestinal barrier function.</description><subject>Animals</subject><subject>Cell Line</subject><subject>Cells</subject><subject>Colon</subject><subject>Colon - cytology</subject><subject>Epithelial Cells - physiology</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Humans</subject><subject>Leptin - physiology</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mucin 5AC</subject><subject>Mucin-2</subject><subject>Mucin-3</subject><subject>Mucin-4</subject><subject>Mucins - biosynthesis</subject><subject>Mucins - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - physiology</subject><subject>Protein Kinase C - physiology</subject><subject>Proteins</subject><subject>Rats</subject><subject>Receptors, Cell Surface - physiology</subject><subject>Receptors, Leptin</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><issn>0193-1857</issn><issn>1522-1547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNpFkUtv2zAQhImgQey6uedUED1H7pIURekYGH0EdhEf0rNAUSubhiSqpITU_6I_OfQD6Gmxi5lvgB1CHhgsGZP8qz4MO7sEgIItOYC6IfN45gmTqfpA5sAKkbBcqhn5GMIh6iRn7I7MmEoLCYLPyb8NDqPtaefqqdUjBjrukeLfwWMI1vXUNTSg8ThiTXVf0w67yuseEx2CM1af7t1kbB9oxBjXut4aioONnNbqlhps20CrIx2132HM2tHtevVIt89i_XhG_nrarumgx_2bPoZP5LbRbcD761yQ39-_va5-JpuXH8-rp01iRAFj0qQ8U00OkGFd5ZgVRQ4pyyuTyqZgmTJx01JpKSSvRSYhz402oBuOisnciAX5cuEO3v2ZMIzlwU2-j5ElF1wWoACiCC4i410IHpty8LbT_lgyKE8NlOcGynMD5amBaPl85U5Vh_V_w_Xl4h2G44Kt</recordid><startdate>20070701</startdate><enddate>20070701</enddate><creator>El Homsi, Mahmoud</creator><creator>Ducroc, Robert</creator><creator>Claustre, Jean</creator><creator>Jourdan, Gérard</creator><creator>Gertler, Arieh</creator><creator>Estienne, Monique</creator><creator>Bado, André</creator><creator>Scoazec, Jean-Yves</creator><creator>Plaisancié, Pascale</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20070701</creationdate><title>Leptin modulates the expression of secreted and membrane-associated mucins in colonic epithelial cells by targeting PKC, PI3K, and MAPK pathways</title><author>El Homsi, Mahmoud ; Ducroc, Robert ; Claustre, Jean ; Jourdan, Gérard ; Gertler, Arieh ; Estienne, Monique ; Bado, André ; Scoazec, Jean-Yves ; Plaisancié, Pascale</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-f4267f8006edb8e69980418bc45f9167c041a57a5352d365088cac0af2e7158c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>Cells</topic><topic>Colon</topic><topic>Colon - cytology</topic><topic>Epithelial Cells - physiology</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Humans</topic><topic>Leptin - physiology</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mucin 5AC</topic><topic>Mucin-2</topic><topic>Mucin-3</topic><topic>Mucin-4</topic><topic>Mucins - biosynthesis</topic><topic>Mucins - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - physiology</topic><topic>Protein Kinase C - physiology</topic><topic>Proteins</topic><topic>Rats</topic><topic>Receptors, Cell Surface - physiology</topic><topic>Receptors, Leptin</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>El Homsi, Mahmoud</creatorcontrib><creatorcontrib>Ducroc, Robert</creatorcontrib><creatorcontrib>Claustre, Jean</creatorcontrib><creatorcontrib>Jourdan, Gérard</creatorcontrib><creatorcontrib>Gertler, Arieh</creatorcontrib><creatorcontrib>Estienne, Monique</creatorcontrib><creatorcontrib>Bado, André</creatorcontrib><creatorcontrib>Scoazec, Jean-Yves</creatorcontrib><creatorcontrib>Plaisancié, Pascale</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>El Homsi, Mahmoud</au><au>Ducroc, Robert</au><au>Claustre, Jean</au><au>Jourdan, Gérard</au><au>Gertler, Arieh</au><au>Estienne, Monique</au><au>Bado, André</au><au>Scoazec, Jean-Yves</au><au>Plaisancié, Pascale</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leptin modulates the expression of secreted and membrane-associated mucins in colonic epithelial cells by targeting PKC, PI3K, and MAPK pathways</atitle><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><date>2007-07-01</date><risdate>2007</risdate><volume>293</volume><issue>1</issue><spage>G365</spage><epage>G373</epage><pages>G365-G373</pages><issn>0193-1857</issn><eissn>1522-1547</eissn><coden>APGPDF</coden><abstract>Mucins play an essential role in the protection and repair of gastrointestinal mucosa. We recently showed that luminal leptin strongly stimulated mucin secretion in vivo in rat colon. In the present study, we challenged the hypothesis that leptin may act directly on goblet cells to induce mucin expression in rat and human intestinal mucin-producing cells (DHE and HT29-MTX). The endoluminal effect of leptin was also studied in vivo in rat perfused colon model. The presence of leptin receptors was demonstrated in the two cell lines by Western blot and RT-PCR. In rat DHE cells, leptin (0.01-10 nmol/l, 60 min) dose dependently increased the secretion of mucins (210 +/- 3% of controls) and the expression of Muc2, Muc3, and Muc4 (twofold basal level) but not of Muc1 and Muc5AC. Luminal perfusion of leptin (60 min, 0.1-100 nmol/l) in rat colon also increased the mRNA level of Muc2, Muc3, and Muc4 but not of Muc1. In human HT29-MTX cells, leptin (0.01-10 nmol/l, 60 min) dose dependently enhanced MUC2, MUC5AC, and MUC4 mRNA levels. These effects were prevented by pretreatment of cells with the leptin mutein L39A/D40A/F41A, which acts as a receptor antagonist. Finally, pathway inhibition experiments suggest that leptin increased mucin expression by activating PKC-, phosphatidyl inositol 3-kinase-, and MAPK-dependent pathways but not the JAK/STAT pathway. In conclusion, leptin may contribute significantly to membrane-associated and secreted mucin production via a direct stimulation of colonic epithelial cells and the activation of leptin receptors. These data are consistent with a role for leptin in regulation of the intestinal barrier function.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>17495032</pmid><doi>10.1152/ajpgi.00091.2007</doi></addata></record> |
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| ispartof | American journal of physiology: Gastrointestinal and liver physiology, 2007-07, Vol.293 (1), p.G365-G373 |
| issn | 0193-1857 1522-1547 |
| language | eng |
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| source | American Physiological Society Free |
| subjects | Animals Cell Line Cells Colon Colon - cytology Epithelial Cells - physiology Gene expression Gene Expression - drug effects Humans Leptin - physiology MAP Kinase Signaling System - physiology Mucin 5AC Mucin-2 Mucin-3 Mucin-4 Mucins - biosynthesis Mucins - metabolism Phosphatidylinositol 3-Kinases - physiology Protein Kinase C - physiology Proteins Rats Receptors, Cell Surface - physiology Receptors, Leptin RNA, Messenger - metabolism Rodents |
| title | Leptin modulates the expression of secreted and membrane-associated mucins in colonic epithelial cells by targeting PKC, PI3K, and MAPK pathways |
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